The National Institutes of Child Health and Human Development awarded Phase I and Phase II Small Business Innovative Research Grants to develop The Visible Embryo. Initally designed to evaluate the internet as a teaching tool for first year medical students, The Visible Embryo is linked to over 600 educational institutions and is viewed by more than one million visitors each month.

Today, The Visible Embryo is linked to over 600 educational institutions and is viewed by more than 1 million visitors each month. The field of early embryology has grown to include the identification of the stem cell as not only critical to organogenesis in the embryo, but equally critical to organ function and repair in the adult human. The identification and understanding of genetic malfunction, inflammatory responses, and the progression in chronic disease, begins with a grounding in primary cellular and systemic functions manifested in the study of the early embryo.

The World Health Organization (WHO) has created a new Web site to help researchers, doctors and
patients obtain reliable information on high-quality clinical trials. Now you can go to one website and search all registers to identify clinical trial research underway around the world!

Disclaimer: The Visible Embryo web site is provided for your general information only. The information contained on this site should not be treated as a substitute for medical, legal or other professional advice. Neither is The Visible Embryo responsible or liable for the contents of any websites of third parties which are listed on this site.

Content protected under a Creative Commons License.

No dirivative works may be made or used for commercial purposes.

CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development

Researchers have induced human embryonic stem cells to organize into a 3D structure similar to the human cerebellum.

Researchers at the RIKEN Center for Developmental Biology in Japan have succeeded in inducing human embryonic stem cells to self-organize into a 3D structure similar to the human cerebellum, providing them with tantalizing clues in their attempts to create neural structures in the lab.

One of the primary goals of stem-cell research is to be able to replace damaged body parts with tissues grown from stem cells before those cells differentiate into specialized tissues. For the nervous system, this is particularly challenging because not only do neurons need to be generated, but they must be coaxed to connect to each other in very specific patterns.

RIKEN researchers have taken up this challenge and published their work in Cell Reports. In it, they detail how applying several signaling molecules into three-dimensional cultures prepared from human embryotic stem cells, prompts the cells to differentiate into functioning cerebellar neurons. These neurons self-organize to form the dorsal/ventral (back to front) pattern and multi-layered structure found in the natural developing human cerebellum.

Expanding on their previous work with mice, the researchers began cultures of human embryonic stem cells grown using fibroblast growth factor 2 (FGF2). These cell cultures differentiated into the midbrain-hindbrain region — the cerebellum — within three weeks. That growth was followed by formation of the developing nervous system specific to the cerebellum — within five weeks. Lastly, all types of neuronal cells found only in the cerebellum likewise grew from the cultured stem cells.

After being cultured for about 15 weeks, the cells' electrophysical signals were measured and found to have the correct currents and inhibited receptors needed for normal cerebellar function. Function had truly developed along with structure.

Some FGF2-treated cells also expressed markers for the rhombic lip — the structure where granule cells develop and from which they migrate; and, by week seven, a marker specific to migrating granule precursor cells appears. These cells were oserved to migrate and extend fibers that bent to form the T-shape characteristic of granule cell parallel fibers.

Where neurons form and locate in relation to each other is critical in the developing brain. Early in cerebellar development, cell types distribute unevenly from top to bottom, and dorsal-ventralyl (back to front).

Like chefs experimenting with recipes, researchers tested several factors and found that adding FGF19 around day 14 to the FGF2 treated cells caused several flat oval neuroepithelial cells to form by day 35, expressing dorsal (back) specific markers on the outside and ventral (front) specific markers on the inside. By adding stromal cell-derived factor 1 (SDF1) between days 28 and 35, they were able to generate a continuous neuroepithelial structure with dorsal-ventral polarity.

SDF1 also induced two other important structural changes: (1) the dorsal region spontaneously developed three layers along the dorsal-ventral axis, the 1. ventricular zone, a 2. Purkinje-cell precursor zone, and a 3. rhombic lip zone. And (2) at the one end of the neuroepithelium, a region developed of progenitors and granule and deep cerebellar nuclei projection neurons and negative for Purkinje-cell markers, whose origins could be traced to the rhombic lip zone of the cerebellar plate.

"The principles of self-organization that we observed here are important for the future of developmental biology. Attempts to generate the cerebellum from human iPS cells have now been met with some success. These patient-derived cerebellar neurons and tissues will be useful for modeling cerebellar diseases such as spinocerebellar ataxia."

Abstract
During cerebellar development, the main portion of the cerebellar plate neuroepithelium gives birth to Purkinje cells and interneurons, whereas the rhombic lip, the germinal zone at its dorsal edge, generates granule cells and cerebellar nuclei neurons. However, it remains elusive how these components cooperate to form the intricate cerebellar structure. Here, we found that a polarized cerebellar structure self-organizes in 3D human embryonic stem cell (ESC) culture. The self-organized neuroepithelium differentiates into electrophysiologically functional Purkinje cells. The addition of fibroblast growth factor 19 (FGF19) promotes spontaneous generation of dorsoventrally polarized neural-tube-like structures at the level of the cerebellum. Furthermore, addition of SDF1 and FGF19 promotes the generation of a continuous cerebellar plate neuroepithelium with rhombic-lip-like structure at one end and a three-layer cytoarchitecture similar to the embryonic cerebellum. Thus, human-ESC-derived cerebellar progenitors exhibit substantial self-organizing potential for generating a polarized structure reminiscent of the early human cerebellum at the first trimester.